Summary Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, and present a clinical challenge for which existing treatments have limited efficacy. Existing clinical evidence suggests treatments that simultaneously address symptoms of both PTSD and AUD should be more efficacious than treating either disorder in isolation. The overlap in the neurobiological basis of PTSD and AUD (involving alterations in incentive salience, stress/negative affect, and executive control network functioning) suggests that there could be treatments that would effectively treat both disorders. However, there is no pharmacotherapy or psychotherapy treatment that is clearly effective for both disorders. Topiramate, an FDA-approved anticonvulsant with effects on GABAergic and glutamatergic signaling, has demonstrated efficacy in the treatment of AUD in several randomized clinical trials (RCTs), and has also been tested in several open-label and small RCTs for treatment of PTSD with some evidence of effectiveness. Positive results in one open-label trial and one small RCT in patients with co-occurring PTSD and AUD suggest that topiramate may have beneficial effects on symptoms of both PTSD and AUD in this population. Preclinical work also supports the efficacy of topiramate in ameliorating anxiety-like behavior and altered stress response in animal models of stress and chronic alcohol exposure. A recent clinical study demonstrated that the effects of topiramate on alcohol use were moderated by a polymorphism of the GRIK1 gene (coding for the kainate receptor GluK1 subunit), such that significant benefit was found only among rs2832407 C-allele homozygotes. The proposed study, Project 2 of the proposed center, is a double-blind, 2-group randomized controlled trial evaluating the effects of topiramate, in contrast to those of placebo, in patients with comorbid PTSD and moderate-to-severe AUD. The proposed trial will provide one of the first rigorous tests of whether the effects of topiramate in AUD generalize to patients with co-occurring PTSD, and one of the first rigorous tests of whether topiramate has beneficial effects on PTSD symptoms in this population. It will be the first study to test whether the rs2832407 genotype predicts clinical response to topiramate for AUD and PTSD in patients with both disorders. Further, it will contribute to the understanding of topiramate?s mechanisms of action in the co-morbid AUD/PTSD population, and to the discovery of predictors of treatment response. In support of the overall aims of the center, the trial will serve as a platform for studies of topiramate?s effects on brain chemistry and function as measured by MR spectroscopy, fMRI, and EEG (Project 3). Data from Project 2 will also contribute to Overall Center Aims investigating the relationship of plasma biomarkers in Project 2 to plasma biomarkers in Project 1, and the relationship of plasma biomarkers in Project 2 to neuroimaging markers in Project 3.